sar405 and Huntington-Disease

sar405 has been researched along with Huntington-Disease* in 1 studies

Other Studies

1 other study(ies) available for sar405 and Huntington-Disease

ArticleYear
Optimization of Potent and Selective Ataxia Telangiectasia-Mutated Inhibitors Suitable for a Proof-of-Concept Study in Huntington's Disease Models.
    Journal of medicinal chemistry, 2019, 03-28, Volume: 62, Issue:6

    Genetic and pharmacological evidence indicates that the reduction of ataxia telangiectasia-mutated (ATM) kinase activity can ameliorate mutant huntingtin (mHTT) toxicity in cellular and animal models of Huntington's disease (HD), suggesting that selective inhibition of ATM could provide a novel clinical intervention to treat HD. Here, we describe the development and characterization of ATM inhibitor molecules to enable in vivo proof-of-concept studies in HD animal models. Starting from previously reported ATM inhibitors, we aimed with few modifications to increase brain exposure by decreasing P-glycoprotein liability while maintaining potency and selectivity. Here, we report brain-penetrant ATM inhibitors that have robust pharmacodynamic (PD) effects consistent with ATM kinase inhibition in the mouse brain and an understandable pharmacokinetic/PD (PK/PD) relationship. Compound 17 engages ATM kinase and shows robust dose-dependent inhibition of X-ray irradiation-induced KAP1 phosphorylation in the mouse brain. Furthermore, compound 17 protects against mHTT (Q73)-induced cytotoxicity in a cortical-striatal cell model of HD.

    Topics: Animals; Ataxia Telangiectasia Mutated Proteins; ATP Binding Cassette Transporter, Subfamily B, Member 1; Disease Models, Animal; Dogs; Humans; Huntington Disease; Madin Darby Canine Kidney Cells; Mice; Neuroprotective Agents; Proof of Concept Study

2019